This application addresses Broad Challenge Area (08): Genomics and specific Challenge Topic, 08-HL-104: Assess Genetic Variation in African Americans and determine its effect on disease. Coronary artery disease (CAD) is a leading cause of death worldwide and the largest killer in the United States. The goal of this study is to determine the role of structural variation in the genome (e.g., copy number variants, CNVs) contributing to subclinical cardiovascular disease (CVD) risk. This application proposes the "MESA CNV" ancillary study to determine the extent of genetic contribution to variation in coronary artery calcium (CAC), carotid artery wall thickness (IMT), and risk factors (HDL, LDL) in non- majority populations. While there are some studies investigating the genetics of coronary calcification, subclinical atherosclerosis and risk factors, the vast majority of studies involve SNP genotyping in Caucasian populations. The current proposal is unique for its combination of multiple measures of subclinical atherosclerosis and in its emphasis on non-majority U.S. ethnic groups and families and the role of structural genetic variants. Using the resources of the MESA Family Study, we propose to test the hypothesis that CNVs are located in selected regions of the genome and will contribute to the genetic risk for atherosclerosis. Further, a subset of the CNVs may reside in regions already identified by the existing GWAS studies and, therefore, increase the likelihood that the candidate gene may have a specific function in regulation, thereby identifying potential therapeutic targets. It is important to target the entire genome to identify potential CNV-influenced atherosclerosis risk loci. This project proposes to perform genomic evaluation of structural variants (CNVs) that may modify risk for atherosclerosis and have effects on its correlated phenotypes and risk factors. Some known CNVs are located near existing CVD susceptibility regions identified by linkage and association scans. This project will, in itself, provide important clues for fine mapping, gene action and function. The project is comprehensive, as it targets the entire genome for implication of CNVs on risk in atherosclerosis. It is highly innovative in its use of a unique resource of MESA African-American and Hispanic families previously genotyped, and proposes to perform comprehensive mapping and analysis to identify regional location, gene identification, and potential causal variant(s) associated with structural variation. This study will consist of two components, evaluation of common CNVs and detection of rare CNVs on atherosclerosis risk. The common CNV analysis will take advantage of the latest advances in the understanding human structural variation, combined with a powerful experimental design using family data, to extend the set of common CNVs that can be tested for CVD/atherosclerosis association. The large sample size of families will also provide an unprecedented statistical power to identify new associations with common CNVs. The rare CNV analysis will investigate a set of genetic variants so far unexplored by association studies: rare variants (minor allele frequency as low as 0.5% in the cohort) but with strong effects on disease risk (odds ratio in the 2-3 range). Owing to these strong effects, such associated rare variants will be outstanding candidates for future functional studies designed to improve our understanding of etiology. The proposed research will greatly advance the field of CVD and genetic basis of atherosclerosis and will provide a foundation for future functional studies. As part of the MESA Study (and MESA SHARe), these data will be coupled with the anticipated MESA genome-wide association scan using SNPs throughout the genome. In addition, consistent with the NHLBI regulations on genome-wide studies, all data will be deposited for use by the greater scientific community and will be accessible through dbGaP. The project represents an extension of the research performed to data by the MESA and MESA Family Study investigators and will be possible only through this collaborative effort. Atherosclerosis is a complex autoimmune disorder that arises from the action of multiple genetic and environmental risk factors with significant burden to the public health of the United States through its role in clinically significant events (heart disease, stroke) and increased morbidity/mortality. This research proposes to scan the human genome in order to identify structural variants (copy number variants, CNVs) that are associated with risk of atherosclerosis. Identification of genetic risk factors for atherosclerosis is the first step in risk prediction, intervention and developing therapeutics for prevention.